Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q1 2025 Earnings Call Transcript

Ultragenyx Pharmaceutical Inc. (NASDAQ:RARE) Q1 2025 Earnings Call Transcript May 6, 2025

Ultragenyx Pharmaceutical Inc. misses on earnings expectations. Reported EPS is $-1.57 EPS, expectations were $-1.54.

Operator: Good afternoon, and welcome to the Ultragenyx First Quarter 2025 Financial Results Conference call. At this time, all participants are in a listen-only mode. At the end of the prepared remarks, you will have an opportunity to ask questions during the Q&A portion of the call. It is now my pleasure, to turn the call over to Joshua Higa, Vice President of Investor Relations.

Joshua Higa: Thank you. We have issued a press release detailing our financial results, which you can find on our website at ultragenyx.com. Joining me on this call are Emil Kakkis, Chief Executive Officer and President; Erik Harris, Chief Commercial Officer; Howard Horn, Chief Financial Officer; and Eric Crombez, Chief Medical Officer. I’d like to remind everyone that during today’s call, we will be making forward-looking statements. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. Please refer to the risk factors discussed in our latest SEC filings. I’ll now turn the call over to Emil.

Emil Kakkis: Thanks, Josh and good afternoon everyone. In the first quarter, we continued to make meaningful progress across one of the most productive commercial development pipelines in rare diseases. Our commercial team delivered a strong quarter that, puts us in position to have another year with meaningful revenue growth. Our early investments in high performing teams, have helped generate substantial revenue growth while we commercialize our products outside of the United States. At the same time, we are preparing to launch our next set of programs in the U.S. and around the world. Our development teams have advanced our large and late stage programs as well. For the UX143 in osteogenesis imperfect, patients in the Phase 3 phase have now been enrolled for at least a year, and the process begun to clean and lock the databases for our second interim analysis.

For GTX-102 and Angelman syndrome, the Phase 3 is enrolling efficiently at sites in the United States, Canada, Japan, Germany, Poland and Spain, and data are expected in 2026. For DTX301 and ornithine transcarbamylase deficiency or OTC. The Phase 3 study completed enrollment in the first quarter, and is on track to read out data over the next year. For UX701 and Wilson disease, the study is now enrolling the fourth dose finding cohort that will enable dose selection and transition to the pivotal stage. At the same time, we’re working on two separate BLAs, one currently under review, and the second to be submitted. The DTX401 for GSDIa a BLA submission is on track for mid-2025. After successfully completing the PPQ runs, the qualification laws essentially at our manufacturing facility in Bedford, Massachusetts.

The UX111 for Sanfilippo syndrome BLA under review by the FDA is progressing on schedule as expected. It’s not our standard practice to go into the details of regulatory interactions, but I think it’s meaningful at this current time for investors to be aware that our interaction with the FDA on the UX111 BLA review thus far remain on track. Last month we had our mid cycle review meeting that occurred on the standard timeline. We also know that inspections of the manufacturing facilities, and clinical sites have been scheduled according to normal cadence, and are currently underway. We remain on track for the PDUFA action date of August 18. Going forward, we don’t plan on giving the details of all our regulatory interactions, but we did want to share enough detail for you to remain confident as, we are that the UX BLA review is progressing according to plan.

With that, I’ll turn it over to the rest of the team, to share the details of why 2025 will be a transformational year for Ultragenyx. Eric, I’ll hand it off to you to go through the commercials team’s execution in the first quarter.

Erik Harris: Thank you, Emil and good afternoon everyone. In the first quarter, the commercial organization continued building on the momentum that we saw at the end of 2024. Starting with Crysvita in Latin America, where we lead commercial operations, our team generated approximately 40 new start forms that, led to approximately 40 patients on reimbursed therapy. We now have approximately 775 patients on commercial product in the region. As the team continues to exceed our expectations for Crysvita, physicians in the region consistently tell us how well their patients feel on therapy, which has led to an increasing number of doctors writing prescriptions for multiple patients. We expect growth in the region to continue following the successful negotiation of reimbursement, from the Brazilian and Mexican authorities, which are the two largest payers in the region, and continued expansion in other Central and South American countries.

In the United States, our partner Kyowa Kirin is leading commercialization for Crysvita. The first quarter 2025, revenue was supported by increasing new start forms and new patients on reimbursed therapy. It is fulfilling to see that adults around adult demand – it is fulfilling to see that adults around – adults or have exceeded the make-up more than half – make up more than half of patients on therapy. Considering the skepticism around adult demand at launch. We expect 2025 U.S. Crysvita revenue, to continue growing as they work to identify new pediatric and adult patients with SLH, and convert them to treatment. Moving on to Dojolvi in the United States, growth of new start forms in the first quarter continued to steadily increase, just as we have seen in prior quarters.

Our team generated approximately 30 new start forms, and added approximately 25 new patients to reimburse therapy. This brings the total since launch in 2020, to almost 600 patients on reimbursed therapy. The split between pediatric and adult patients, continues to be approximately 65% PEs and 35% adults. Also, the number of new prescribers continued to grow in the first quarter, with approximately 270 unique prescribers. For Dojolvi across the EMEA region, there are over 260 patients treated under named patient sales across the region. The majority of demand is from France, but we are receiving an increasing number of requests from other countries within the EMEA region, including the Middle East. The demand for this product is quite strong in this region, especially given we are not actively marketing the therapy, and simply responding to named patient requests.

I’ll close with a few comments on Evkeeza, which we began commercializing in our territories outside of the U.S. in 2023. In the EMEA region, we have patients on reimbursed therapy from the majority of major countries. We now have treated approximately 250 patients, adding more than 50 since the beginning of the year, across 15 countries in the region. This is the result of our commercialization efforts, and response to named patient requests, as we continue to successfully navigate the country-by-country pricing negotiations. In Japan, the team continues to build on the launch momentum following the pricing and reimbursement approval that we received last year. In Canada, we are continuing pricing negotiations with government health authorities, and have secured reimbursement agreements with three of the four major private insurers.

Over time, we expect Evkeeza revenue, to contribute more meaningfully to total revenue, as we continue to successfully launch this important product outside of the United States. As I have mentioned on previous earnings calls, we continue to expect quarter-to-quarter variability in revenue, primarily due to uneven ordering patterns for Crysvita and LatAm, but we remain confident in the growing underlying demand, for all of our products around the world. With that, I’ll turn the call to Howard to share more details on our financial results, and guidance.

Howard Horn: Thanks Eric, and good afternoon everyone. I’ll focus on first quarter 2025 financial results, and guidance for the year, starting with revenue. In the first quarter of 2025, we reported $139 million, representing 28% growth over the first quarter of 2024. Crysvita contributed $103 million, including $41 million from North America, $55 million from Latin America and Turkey, and $7 million from Europe. In total, this represents 25% growth over 2024. If you focus on Latin America and Turkey, where we are responsible for generating sales, this represents 52% growth over 2024. Turning now to Dojolvi, it contributed $17 million consistent with its expected steady growth trajectory. Evkeeza contributed $11 million as demand continues to build following launches in our territories, outside of the United States and Mepsevii contributed $8 million, as we continue to treat patients in this ultra-rare indication.

Total operating expenses for the quarter were $282 million, which included R&D expenses of $166 million, SG&A expenses of $88 million and cost of sales of $29 million. Operating expenses included non-cash stock-based compensation of $40 million. For the quarter, net loss was $151 million or $1.57 per share. As of March 31, we had $563 million in cash, cash equivalents and marketable securities, which reflects $45 million in cash payments made for two milestones during the first quarter of 2025 that, were achieved in the fourth quarter of 2024. Specifically $30 million for a GTX-102 Phase 3 study milestone and $15 million for an Evkeeza sales milestone. In the first quarter of 2025, net cash used in operations was $166 million. Recall in the first quarter of the year, we typically use more operating cash than in the subsequent three quarters, because it includes items like the payment of annual bonuses.

In addition, first quarter net cash used in operations also included the $30 million GTX-102 development milestone payment I mentioned earlier. Net cash used in operations is expected to decrease in the remaining quarters of this year, and is expected to total less than what we used in 2024, as we continue on our pathway to full year GAAP profitability in 2027. Shifting to revenue guidance for 2025, we are reaffirming the guidance we gave in February. Total revenue is expected to be between $640 million and $670 million, which represents 14% to 20% growth over 2024. Drivers include increasing demand for our products in Latin America, continued penetration of the pediatric and adult XLH markets in the U.S., and growth from Evkeeza in Europe and Japan.

Crysvita revenue is expected to be between $460 million and $480 million, which includes all regions and all forms of Crysvita revenue to Ultragenyx. This range represents 12% to 17% growth over 2024. Dojolvi revenue is expected to be between $90 million and $100 million, which represents 2% and 14% growth over 2024. As in prior years, our Dojolvi projections represent a blend of faster growth in countries, where we commercialize and lower growth in countries, where we respond to named patient requests. Lastly, with respect to tariffs, the landscape continues to evolve. We are actively monitoring and evaluating multiple potential scenarios, based on what we see currently, we do not expect to have a material exposure, for any of our products, including Crysvita.

With that, I’ll turn the call to our CMO, Eric Crombez, who will provide an update on our key clinical data readouts expected this year.

Eric Crombez: Thank you, Howard and good afternoon everyone. I’ll provide some brief operational updates on our late stage programs, and review our upcoming clinical milestones. Starting with UX143 for the treatment of osteogenesis imperfecta. The Phase 3 ORBIT study, continues to progress well and as we noted earlier in the year, the safety profile is similar to what was observed in Phase 2. Based on the Phase 2 data we previously shared, we are confident that the study will show a clinically and statistically significant reduction in analyzed fracture rate, at either the second interim or final analysis. The ORBIT and COSMIC studies, will both have an interim analysis midyear, after all patients have been on therapy for at least 12 months.

The data readouts will be led by ORBIT, meaning that if ORBIT clears the P value threshold of less than 0.01, we will look to see if COSMIC has cleared the same P value threshold of less than 0.01. If ORBIT progresses to full study completion in the fourth quarter of this year, COSMIC will also continue to a data readout, to align with the ORBIT data readout without spending alpha at this interim assessment. Moving to GTX-101 for the treatment of Angelman Syndrome, we have set an ambitious goal of enrolling a 120 patient pivotal study in less than one year. I’m proud to report that we are on track to achieve this goal, and we are actively working with sites in the U.S., Europe and Japan to enroll patients. We’ve also made progress finalizing the Aurora protocol, which will study younger and older patients and those with other mutations.

We expect to take this protocol through the regulatory process, and begin enrollment later this year. Next DTX401 for the treatment of glycogen storage disease type 1a. In our press release today, we shared some of the additional crossover data that will be included in our BLA filing midyear. During the crossover period, patients demonstrated even greater reductions in total daily cornstarch at their last visit, compared to baseline in both the ongoing DTX401 group and the placebo crossover to DTX401 group. Patients in the DTX401 group, demonstrated a 60% reduction in daily cornstarch at their last visit, with a mean follow-up of 120 weeks. This is a substantial and continued reduction, compared to the 41% reduction in daily cornstarch observed at week 48.

Patients in the placebo to DTX401 group demonstrated a similar 64% reduction in dated cornstarch at their last visit, where the mean duration on therapy with DTX401 was 69 weeks. Patients in both groups, have demonstrated statistically and clinically meaningful reductions in daily cornstarch requirements, demonstrating continued benefit from this gene therapy over time. DTX401 also continues to demonstrate a consistent and acceptable safety profile, with no new safety signals identified. The manufacturing process at our Bedford, Massachusetts facility is going well, and we recently successfully completed our process performance qualification runs. While the tech transfer from a CDMO to our facility was done quickly and efficiently, it did impact our BLA submission timing.

We were able to capitalize on this opportunity to collect more clinical data resulting in an even stronger clinical and CMC filing package that we will submit to the FDA midyear. Finally, I’ll touch on UX701, for the treatment of Wilson disease. As noted in our press release today, we have recently begun enrolling patients into a fourth dosing cohort, at a dose of 4.0e13. These patients will receive a new immunomodulation regimen with rituximab and tacrolimus in addition to the corticosteroid regimen used in the previous cohorts. We expect that the combination of enhanced immunomodulation regimen, and a moderately higher dose could achieve the broad response needed to select a dose, to take forward into the pivotal Stage 2 of this study. Also noted in our press release today, the pivotal Stage 2 portion of the protocol, was amended to a 52-week randomized open-label active control design.

The open-label design allows for patients and investigators to be more comfortable with discontinuation of standard-of-care consistent with their experience in our other metabolic gene therapy programs. The Stage 2 primary endpoints are largely the same as before, but instead of comparisons to placebo they are now compared to the active control arm. Specifically, we will be looking at the change in 24 hour urinary copper from baseline to week 52, and percent reduction in standard-of-care by week 52. I’ll now turn the call back to Emil, to provide some closing remarks.

Emil Kakkis: Thank you, Eric. Over the first part of the year, we made tremendous progress executing on all fronts. Patients in both UX143 for osteogenesis imperfecta studies, have now been enrolled for at least 12 months. And this enables our teams to start the process of cleaning and locking the databases that will be shared with the data monitoring committee in the next few months. The feedback we hear from investigators, with patients in the Phase 2 portion of the ORBIT study, gives us confidence that the treatment effect with setrusumab and osteogenesis imperfecta is transformative for these patients. In closing, we expect 2025 to be the most productive year in our company’s history. With the commercial organization generating $640 million to $670 million in revenue, and the development organization managing one BLA under review, a second BLA submitted in the middle of the year, and multiple Phase 3 studies enrolling or reading out data, we are in prime position to lead the future of rare disease medicine.

With that, let’s move on to your questions. Operator, please provide the Q&A instructions.

Q&A Session

Operator: Thank you. [Operator Instructions] Our first question is from Yaron Werber with TD Cowen.

Yaron Werber: Great. Thank you so much for taking my question. Not surprisingly, it’s going to be about setrusumab. The second interim analysis and sort of one question in two parts. Maybe the first one. Emil, you’ve talked recently about dispersion in the study, and that’s something that when we look at the prior data in the Phase 2, the dispersion is not really shown. We can tell that there’s variability in how many fractures patients have at baseline. So can you maybe explain to us what do you mean by dispersion? Maybe why it’s important. And then secondly, when we look at the 67% fracture reduction, if I recall correctly, that was at around six or seven months. Can you give us a sense, kind of what it was seeing when it was at 14 months. The latest cut that was at ASBMR? Thank you.

Emil Kakkis: Sure Yaron. Thank you. So I don’t know, if I actually use the word dispersion, because that’s like a statistician term. I usually mention variation, that there is a variation in the analyzed fracture rate at baseline. And we know we have people who can have more than three fractures a year, or any fracture greater than three and some less. And we stratify in the trials that those that are greater than three would be stratified equally, between the treatment and placebo group, as would the ones below that. But how it’s distributed can have some impact on the probability of success, just because variation is what really affects. So we haven’t talked through that distribution, or shown it, but there is a fairly wide range of fractures baseline.

Now, the statistical method we’re using, the negative binomial, will capture the AFRs at baseline as a covariable meaning. We’ll help correct for that in the way we analyze it, which help assure that it doesn’t have a substantial impact. We’re also stratifying by age in trial. So we, we’re doing a number of things, which will help reduce variation. But there is a lot of variation in severity and fracture frequency. And we think we’ve done what we can. But that might be one reason why you might not hit IA2. We think we have a good shot of hitting IA2 based on everything we know. But we are very strongly positive on the trial, whether IA2 or the end, that’s going to be successful. Let’s talk about the fracture reduction. We announced Phase 2 data after six months or so and showed a 67% reduction with a P value of 0.04.

Now, when we did the 14 month cut of the same 24 patients, we had the same 67% reduction in fracture frequency median. And the P value though, was 0.0014. You might be wondering, well, how is the number the same? I would look at this and think of it as a line of accumulated fractures. The accumulated fractures in in one group is going up at a steep rate and the slope of the other line is only 67% less, right. So the two lines are running apart from each other. If you cut the two lines earlier, they’re not as far apart, but if you wait for those two lines to progress further, they’re further apart. The slopes are still 67%, the same treatment effect size, but the P value is better. So what’s happening at interim one, is that they may not have separated far enough yet.

And it would only happen if we had a lot of fractures, but by the second time we’ll have run longer, then we should have much better separation. So from that analysis, it suggests that we could hit it IA2. It’s a reasonable shot. Now, we did do an analysis of our Phase 2 data. For those that have heard this from me, we did take the same data, analyze the patients as if their prior year, was on placebo and compared to their current year on treatment. And with the negative binomial, you get the same 60s, mid-60s percent kind of reduction with a good P value. So just to be clear, if you do it by the method we’re using in Phase 3, you get a very similar result. Just because some people wondered whether the different statistical approach would matter.

So variability is an issue. Dispersion or statistical version of it we could go into. But I think the key thing, I would say is that I think we have plenty of power to succeed in the study, whether it’s IA2 or at the end. All right, let’s go on.

Operator: Our next question is from Tazeen Ahmad with Bank of America.

Tazeen Ahmad: Hi, good afternoon. Thanks for taking my question. Emil, I also have a question on OI, but this would be if the study moves to a third interim read, what’s your view of the likelihood of success? You’ve talked now multiple times about confidence in the molecule overall, and we would agree that the drug is active. But if the study moves to the third interim, what would be a reason to be concerned that it would not work at the third interim? Thanks.

Emil Kakkis: Right. Well, it won’t be. The next assessment is the final assessment for the study and that P value threshold will be 0.04. So it would be a lot easier to hit 0.04. So we think that we will hit one or the other. Based on our experience, what we’ve seen, I don’t think we could miss the 0.04 at that point with 18 months of time. But as always in rare disease programs, the thing you always are battling us is variation, variability in patients. But based on the profound difference in bone marrow density change that we see, that happens within two to three months and the fracture rate effect happens within two to three months, we feel pretty good about IA2 hitting, but confident about overall the study hitting even at the end, if not at the IA2.

So I can’t tell you a reason why, but variation is always the thing that can create complexities. But given that the patient, the program is 159 patients that’s a pretty large study, and the data we’re talking about before was ’24. So I think, we’ve got a lot of power in there but and we’ve done everything we can to manage variations. So I feel good about we’ll hit it this year either at 0.01 or 0.04 after 18 months.

Operator: Our next question is from Gena Wang with Barclays.

Gena Wang: Thank you for taking my questions. Maybe a little bit switch gear a little bit, the non-fundamental questions. I think it was a recent CBER nomination, Vinay Prasad and I think there is a lot of uncertainties. We saw massive sell off in the biotech sector, and so Avio [ph] maybe wanted to get your thoughts like, where do you see that could be potential impact to specifically in the rare disease space, and how do you deal with, or what would be the strategy you have dealing with this situation? And there’s still open questions, a lot of uncertainty there. And my second question also go back to the OI. I think a recent discussion we had. You did mention that like over maybe 80% of patients have a baseline bisphosphonate, and then the washout period in the late enrollment period.

You did skip the washout period. So would that be any concern regarding say the placebo fracture rate picking up at some point? Would that have a delay rather than say 12 months, would I need a little bit longer time so that we can see the placebo on the factory [ph] start to pick up?

Emil Kakkis: Very good. So yes, the CBER appointment we don’t think was a good choice. As someone who has argued against accelerated approval for cancer programs, and that may be a concern, I think we’d have to anchor back to the fact that Cary [ph] has been talking about the importance of rare disease approvals, and thinking how to improve and accelerate the process or reduce the time of development. So we’ll have to anchor to that discussion and point he’s made and see what site does. I think for our own program for UX111, we have lots of clinical data in the program. I’m less concerned about it, because of the fact we have clinical data showing efficacy in addition to the biomarker data. And so, I think for us right now we’re not concerned, but I think for industry at large, it’d be important for accelerated approval to be available for a lot of the gene or cell therapies.

And it would be important to McCary’s [ph] public commitment to trying to move these things forward. It’s something that he follows through on. How Prasad will do that, we don’t know, but I think the FDA is very important. The industry supports FDA and their mission, and we just hope that they continue to make good decisions. On the second question, so more than 80%, 90% or something like that were on bisphosphonates in the study, right, Eric? Correct. Yes. And the washout timeframe, is in the one to two-year period. So we’d expect the placebo patients, to have steadily declining frac bisphosphonated theft, and therefore steadily potentially increasing fracture rate as their bone marrow density decline. But we don’t think that effect is really a meaningful effect compared to the dramatic effect on bone marrow density that’s going to happen with setrusumab, right.

Where for the five to 12 group we had a 29% increase, the bone marrow density improvement, the effect on the other groups will not be nearly so large. So what it would do is both groups would have a loss of bisphosphate effect over the period. But remember, setrusumab arm will also have some antiresorptive effect from the drug itself. So if anything, what this will do is increase the rate of separation as time goes on, and improve the power of the study the longer it goes. Do you have anything else to add to that, you think?

Eric Crombez: Just that we didn’t count on this when we were designing the study, empowering the study, we did not account for that effect. So any sense that could be considered an OPSI yes?

Gena Wang: Very good, thank you.

Operator: Our next question is from Salveen Richter with Goldman Sachs.

Lydia Erdman: Hi, this is Lydia on for Salveen. Thanks so much for taking our questions and congrats on all the progress. Just maybe another one on the setrusumab. Could you just discuss how you plan to message the outcome of the interim to the street, and whether you intend to share any data with this update? Thanks so much.

Emil Kakkis: Yes. So when the DMC has presented the information on ORBIT, if it’s positive, they’ll inform us and we will inform the street of the results. If they inform us that the study needs to go to the end, we’ll also inform the street that the study is continuing to the end. So if you haven’t heard from us, because the decision hasn’t happened yet and a decision either it’s moving forward to the final assessment, or it’s ending at the interim will be clear. We haven’t set what all the data might be in or not in that release, but different from interim one, we are having to fully clean the database for potential filing from that data set. So the timed data would be faster than we have said for the IE1, where we had only partial lock and we had to continue the trial.

So it would be relatively soon after we talk about data. Now, if IA2 is positive, then the COSMIC study will be evaluated. If ORBIT is negative, then we won’t unblind the COSMIC data, and we’ll wait for both studies to go to the next assessment. Okay.

Lydia Erdman: Thanks so much.

Operator: Our next question is from Anupam Rama with JPMorgan.

Malcolm Kuno: Hi. Thanks for taking the question. This is actually Malcolm Kuno on for Anupam. So where are you on your enrollment curve for the Angelman program? And have you opened all of the global sites for the program yet?

Emil Kakkis: Well, I’ll ask Eric to comment on that.

Eric Crombez: Yes. So, like we said, our plan is to fully enroll that study this year. We are committed to that. We have really prioritized that and leverage the experience we had with OI and really enrolling for us for rare disease, a relatively large pivotal trial. So we certainly want to do this as quickly as possible. And yes, our global sites are active and beginning to screen in those patients. So all sites active.

Malcolm Kuno: Excellent. Thank you.

Operator: Our next question is from Kristen Kluska with Cantor.

Kristen Kluska: Hi, good afternoon. You talk about potential variation factors. I wanted to see color about how you’re thinking about the age of the baseline. I know investors tend to focus a lot about the types of OI, but based on some of the BMD data, you’ve shown that the effects could be even superior the younger you treat. And I know the ORBIT trial has a range of about 20 years, so is there anything you’re able to share?

Emil Kakkis: I don’t think we shared the exact enrollment, but the majority of patients are going to be pediatric, and a relatively limited number of older patients. We’re including them in order to allow us, to label for adults as well off that study. If there’s any questions, but the majority of the patients are going to be in the pediatric age range for the program. Is there anything else you think we could offer, Eric?

Eric Crombez: No, I think that covered it.

Emil Kakkis: Yes.

Kristen Kluska: Thanks. And then just to clarify, if IA2 is. If it does hit the analysis, will you also be announcing the same day whether Cosmic was successful as well, or will those updates be separate? Thank you again.

Emil Kakkis: We haven’t said, it depends. They’re not happening. The reviews of both programs are not happening the same day. One will happen and then the other. So we haven’t said yet whether we’d have them both the same day or not. We like to keep you guessing a little bit, right. Why make it too easy?

Operator: Our next question is from Yigal Nochomovitz with Citi.

Yigal Nochomovitz: Hi, thanks. Have you commented at all on the distribution of the types for OI for 1, 3 and 4 for the Phase 2 versus the ORBIT trial? And then also this is a very specific question, but what exactly is the tolerance on these P values? I mean, we’re talking about some pretty small numbers here, so I mean, hypothetically, if it’s like 0.011 on the second interim, is that a fail or a win? I mean, I would. I think I know, but I’m not sure actually. So I’m just curious if you could clarify that level of detail, and whether you were ever told the P value for the first one, the first interim? Thanks.

Emil Kakkis: So, on the OI types, I think we’ve disclosed before that in the Phase 2 study there were seven type 3s and 4s and 17 type 1s. And then because the doctors were then impressed with the results, then they were interested in bringing in their more severe three and four patients. So we ended up with more type threes that we bought. Half the patient are type 3 and 4 are approximately there in the study. So it’s definitely an increase in type 3s and 4s in the Phase 3 study than they were in the Phase 2 study. All right, now, for tolerance, we haven’t set that like how many sig figs of significance? Honestly, I don’t have an answer for you, but I would say if it’s like 0.015 or 0.016, that is not less than 0.01, right.

So it would probably. That would be considered a miss at this point, which means you could be very close to a very good result and still miss and go to the end of the year. Which is why we shouldn’t overreact if there was an issue. But so that’s the basic, the tolerance question. And then the last one was whether it was the P value. And the others we haven’t provided a P value. We were not aware of the P value nor provided one in the interim. The first interim, we were just told that it was study was continuing and no result. So what we know from the prior analysis of Phase 2 though, that the P value was 0.014 at 14 months. So we think there’s a reasonable chance of hitting IA2, pretty good chance of hitting IA2, and a much better chance of hitting IA2 at the 0.01 threshold than there was at IA1 was 0.001.

All right, thank you Yigal.

Yigal Nochomovitz: Thanks.

Operator: Our next question is from Joseph Schwartz with Leerink.

Joseph Schwartz: Hi all, this is Will on for Joe. Thanks for taking our question and congrats on the progress this quarter. So one for us on Angelman. Now with three ASOs that are in or nearing civil development, including the one from Roche that was recently revived. Are you thinking about the evolution of this market, and do you see room for multiple treatment options? And how do you think these assets can potentially further differentiate themselves? And how do you think patients are going to be making decisions from a clinical trial, or commercial therapy perspective? Thank you.

Emil Kakkis: Thank you. Well, we are not usually working in competitive space with a lot of products in the same space. So this will be a new thing. Usually we’re working on first ever treatments in our by ourselves. So it’s definitely a different space. I would say in the regard of these ASOs, ultimately the most potent and effective drug will be the one that will tend to dominate. But that doesn’t mean there might not be a place for other molecules in the space as well. I think they’re very similar in terms of them being intrathecally administered ASOs. But I do believe our drug is the most potent, and has shown that and I think we’ve shown the best long-term data continues improvement over long periods of time. That has been shown for the INS molecule.

The Roche molecule is sort of coming back in development. I am not concerned about, I think that that drug is even less potent, and has other questions marked. So if there’s more than one out there, I think it’ll depend on efficacy and what people can show. I do think that we have, because we expanded our Phase 2 study, and we have almost 70 patients on drug. We’re going to have a pretty big body of kids that, have been on drug several years. I think how those kids are going to do, are going to be probably even more impactful than the Phase 3 study. That will be what people want to see. What’s my future like for my kid if I’m on this? And we know from some of the early patients on there, the first one that actually had words, he had a few words in the first year.

Now she’s speaking a few dozen words, and has continued to gain ground over time. So I think that experience will be really important. I do think we’re in the best position to be the leader in the ASO space. And my hope going down the road that the top three ASO treatments will be our first product, then our second improvement and then the third next gen that comes out, because we intend to be the leaders in Angelman.

Operator: Our next question is from Liisa Bayko with Evercore ISI.

Liisa Bayko: Hi, thanks for taking the question. I just wanted to clarify. Sorry to ask so many questions on setrusumab. Can you give us a little greater sense on where you are in terms of timing what happens from here to data, and then I just wanted to understand. Follow-up on an earlier question, if the data reads up positive, do you say it’s positive and then take some time to analyze the data and come back to us with the data, or is that all in one press release? Thanks.

Emil Kakkis: Yes. So on the timing of data, because I think people may, some people may have had an unrealistic expectation that you would clean, lock and analyze the data in a couple weeks or something. But this is an international Phase 3 study and this clean and lock is the entire data set, not just the primary endpoint, the whole thing. Because if it’s positive, we need to go straight to preparing a BLA filing. So there normally takes a Phase 3, around eight weeks of international study to clean a lock a database. Plus there would be some time to analyze and have a DMC meet. So at the time, we find the result we will, there’ll be a much shorter time than we had before in terms of seeing what the data are. We haven’t yet precisely said whether we’ll disclose it together at once, or whether it be an initial read and some further.

So we’re going to leave that open right now. But our expectation is that it’ll be sooner to getting the top line data than it would have been in IA1, where we had some other questions. So hopefully that gives you an idea at least of how it’s going to flow.

Liisa Bayko: Okay, so what I understand what took the IA1 a little bit longer just to understand the differences there that’s my final question please?

Emil Kakkis: What happened to IA1 is that even if the interim was positive, the regulatory authorities wanted to have the majority of patients have at least 12 months of data. So we would have had to keep running the study for a couple months. In other words, if I wanted to hit, we say oh, we’re were far enough along, and so we would then continue collecting data for a couple months until more than half the patients had 12 months of data, and then we would have started and we’ve been doing all the final visits and cleaning locking at that time. So there had been a delay before we clean and lock, so you wouldn’t be able to see the data, for not just two months but probably three to four months, because we have to clean and lock it. So the timeframe here is much faster, because we’re going to clean lock the whole database this time, and we would be able to release top line data sooner than we would have at IA1.

Operator: Our next question is from Luca Issi with RBC Capital.

Luca Issi: Oh great. Thanks so much for taking my question. Congrats on the progress. Maybe just one more on OI. Just to be super, super clear. In a scenario where you actually don’t hit the second interim lock, will the DSMB share with you the P value? Just wondering whether you will have a sense of whether you missed by a narrow margin, or not and then maybe related, is it fair to assume that the PRV for OI is possible only if you hit a second interim? Look, even my understanding is that you need to get approved by the end of 2026 in order to get the PRV. Given that there’s sunset in that program, any context there much appreciated? Thanks so much.

Emil Kakkis: Yes. So if we don’t hit it, we’ll just find out that the study is continuing, and we didn’t hit it. We will not get any P values. We won’t know if it’s close. We do have PIG designation and we’d have to get approved by October. So whatever time frame we file would have to be within the time frame to get approval by October. Obviously IA2 it’s easier. If we have to go to the end of the study, then the time to file would have to be much shorter and the review rapid. But I would also point out too, we do have breakthrough therapy designation for this program. So I think there are reasons why we could be able to accelerate things if need be. But our goal would be to get this filed in time to get a third PRV. Short of that, we certainly have already potentially two PRVs in place.

If 111 gets approved for Sanfilippo and if the DTX 401 gets approved for GSD1A. So I don’t think there’s anyone with potentially three PRVs still in play. Without the reauthorization, I do believe the bill will get reauthorized. I think we’ve had assurances that is true, but I think right now some of the other matters that are top of mind in Capitol Hill that that one will take a little while before it will come up. Let me clarify that.

Luca Issi: Thanks so much.

Emil Kakkis: The 143 PRV is in October 2026. We need approval by October 2026, right. Next question. Thanks, operator.

Operator: Our next question is from Joon Lee with Truist Securities.

Mehdi Goudarzi: Hello, good afternoon, and thanks for taking our question. This is Mehdi on for Joon. So I go on live and follow-up Igor’s question on composition of OI types. So do you agree that setrusumab’s MOA benefits the type 1 patients more than type 4 and 3? This is the question?

Emil Kakkis: Well, I know there’s been some academics saying that, but. And I know some of them, very good academics, but they’re actually incorrect, because we already have data. So it’s not. The theory would be that in type 1 patients you’re deficient in collagen. We don’t have abnormal collagen, therefore, if we just make more bone, it’ll be okay. And the type 3 and 4 have abnormal collagen, therefore it’s not improved. But that’s not actually what we saw. We see both of them have improved reduction of fractures. And in fact, the ones fractures we did see were in type 1 patients, I think were some of the ones not type three to four. So the truth is all of them are improved, because while one’s a deficiency of collagen and one is abnormal collagen, whether deficient or abnormal, the net benefit of making more bone is greater bone strength and reduced fractures.

So it actually works in all three. And historical clinical view of why is going to change, because the truth is that even with abnormal collagen, the bones can be strengthened. We believe in these patients, and that’s what we’ve seen, and that’s in the data from Phase 2. And so we’re confident that the type will not matter. You get the same bone marrow density effect, and the strength improvement will be the same regardless of the collagen mutation.

Mehdi Goudarzi: Thank you very much.

Operator: Our next question is from Maury Raycroft with Jefferies.

Maury Raycroft: Hi. Congrats on the progress, and thanks for taking my question. I’ll ask one on OI as well. Just, I guess, based on what you know about the baseline characteristics and expectations for variation, can you provide any perspective on how you’re thinking about the range of effect sizes on AFR reduction that would be needed to succeed on the second interim?

Emil Kakkis: Yes. So we’ve had that question in various forms of it. Like what’s clinically meaningful for action reduction? I think for clinically meaningful, most people say at least 30%, 40% would be clinically meaningful. The phosphates are probably 20% or less. So anything like 34% or better, we don’t have a sense now for sure what the power would tell us. Just I said before, when the curves separate, they’re linear, essentially. And so, we saw them separate within two to three months of treatment, which means when they get to even just 9%, 10% improvement in bone density, there’s already a separation in fracture frequency, but after that it appears relatively linear. Which tells me then that the percent reduction on the slopes won’t really change that much over time.

And therefore, I don’t think you can think about like, when you hit will determine what percent of production you get. I think you have to think of it more as a slope, and the time is will just depend how far apart the two lines are, how many fractures accumulated in one arm versus the other to give you the power. Does that answer your question?

Maury Raycroft: Yes, it does. I think so it’s helpful perspective. Thank you.

Operator: Our next question is from Laura Chico with Wedbush.

Unidentified Analyst: Hi, thank you very much for taking the question. This is Dylan on for Laura Chico. So for Crysvita, could you extend further on key growth drivers in the quarter and maybe what is helping drive uptake more specifically in the LatAm Turkey regions or I guess what is unique about patient identification efforts in these regions?

Emil Kakkis: Okay, well, Crysvita is growing really well Latin America, but I think it’s growing recognition of how much patients do. But I don’t know Eric, if you had any thoughts on what you say about how why it’s growing in Latin America particularly?

Eric Crombez: Well, as I had stated in the opening remarks that patients are having a good experience with the product, and physicians are now treating more and more of their patients to include adult patients in the LatAm region as well.

Emil Kakkis: Just a little bit about word of mouth and propagation of that. We don’t have a particularly prominent patient diagnosis function in Latin America. There are certain doctors, I mean employees that are doing patient fine, but it’s not quite the same, because we don’t have the same tools in South America that we have in the U.S. like we don’t have the codes, nine codes, 10 codes and other things to help us. But so it’s a little bit more word of mouth, but I think it’s impressive. But I believe the sound feeling of doctors that this is transformative for patients’ means they’re just there they want to get more and more on. When I went down to the meeting last year, the Latin America gazillion meeting on these patients, it was clear difference from the very first meeting we did at launch that every doctor had a story of how their kids were doing and were grateful, excited about it.

And we’re happy to be able to do something for these kids. So I think that mood is good. The fact we’re getting adults on is great too, because we certainly had gotten primarily peds on originally.

Eric Crombez: Yes. So in addition to the strong demand for both pediatric patients and adult patients, as I stated, we have now have reimbursement with the national authorities.

Emil Kakkis: Yes in Brazil.

Eric Crombez: Brazil as well as Mexico.

Emil Kakkis: Yes. That’s what’s really driven it for Brazil and Mexico. Driven a lot of increase in uptake rather than just name patient approach. In Turkey, it’s still under named patient, but same thing’s happening once the doctor starts treating people to see what happened, over a period of a year. They see how their bones are doing, how the kids are doing, they get adamant about getting more kids on and parents who are friends of people find out, and that’s what a good drug will do. Even in an inpatient setting, people hear about a story, and they all want to get something for their kids. So we’re excited about that continued growth of the product internationally. And I think the investment in Latin America and the top tier team and in Turkey, have been rewarded by being able to build a really solid, growing business for the company.

Eric Crombez: And I think that just sets us up well for when we bring setrusumab to the marketplace.

Emil Kakkis: It will, because I think there’s a lot to OI everywhere as well. Thank you for the question.

Operator: Our next question is from Jack Allen with Baird.

Jack Allen: Great, thanks for taking the questions and congratulations on the progress made over the course of the quarter. One more logistical one on setrusumab. Have you pointed investors towards how many of the patients had 12 months of data at that first interim readout? It sounds like it was the minority of patients, but I’d love to hear if you’re willing to put a little bit more finer point on the percentage of patients. And then also on setrusumab. I wanted to ask you about any disclosures you’ve made on the impact that setrusumab has had on bone pain. We recently did a call with a physician who mentioned bone pain is a key symptom for these OI patients, and I’d love to hear any impacts of setrusumab could have there? Thank you.

Emil Kakkis: Okay, I’ll talk a little about the IA1 and maybe you can touch on the repression scale scores or just a little bit about the pain. I guess so, just to understand the enrollment curve. We had a lot of patients enroll in the last two to three months of that trial, right. It was very much a hockey stick. So when we had the minimum was seven months at that time point, we had a lot of people who were at 8, 9, 10 months, right. And a relatively smaller number at the 12 to 17-month timeframe, relatively smaller tail, right. So the vast majority of patients had less than a year at that time. In order to get the majority to have a year, you would take another two months or three months from when the cut was made. Does that make sense?

So it’s a very steep accumulation at the end. A lot of the patients were less than a year then the majority were less than a year at the first interim. So it will be a significant difference in the number of patients that have, let’s say, exposure beyond the two to three-month period where they get the bone effect. So let’s talk about something other infraction. I think it’s actually really important. It’s true for Christina [ph] too, that things other than the bones often are drivers. What’s our thought from what we’ve seen in the Phase 2 data?

Eric Crombez: Yes, no, agree. A pain is a big part of this and certainly very important to patients and important part of the evaluation for the clinical trial. So we are focused on pain comfort subscales, and really focusing more on type of assessments that you would do with sports physical functioning. We are also doing a traditional SF36 to look at this, but definitely following pain over the long-term. In Phase 2, we did hear a lot of improvement there. Anecdotally, we have heard that patients have had a lot of improvement in pain scores.

Emil Kakkis: Yes, I think. Yes, I would say too, based on how kids were feeling, like they’re running, hi, I want to go to sports and stuff. They were feeling different too. I mean, whether pain or fatigue or generally malaise. These two patients also got pretty energized, I think right. And so that’s also what happens with Crysvita, by the way. That’s why Crysvita to pick up was so fast. Kids feel good, parents see it. And I think that’s happening with OI too. I think when your bones get stronger, even a little bit stronger, your body feels it and you know it. So we’re excited about it. When we look at how many patients we have for that program and the fact that it’s more than even with XLH, it’s pretty clear that this program should exceed what we’ve done with Crysvita.

And I think we’ll launch more rapidly. We just, of course, have to get our IA2 or final data in hand and get to a file. But we’re excited about the opportunity being larger than it is. Even with Crysvita, there’s very few times you get to do something amazing like that again. And we’re really thankful to have an opportunity to take on a bone disease like osteogenesis imperfecta and turn it around for patients in the future. Thank you for the question.

Operator: Thank you. There are no further questions at this time. I’d like to hand the floor back over to Joshua Higa, for any closing comments.

Joshua Higa: Thank you. This concludes today’s call. If there are additional questions, please contact us by phone or at ultragenyx.com. Thank you for joining us.

Operator: You may disconnect your lines at this time. Thank you for your participation.